DIABET ZAHART

Diabetul zaharat: O chemare la aciune

Prima cauza de orbirePrima cauza de insuficienta renala si boala renala care necesita dializa si transplantPrima cauza de amputatie24 ori mai frecvente bolile coronariene & strokes la diabetici fata de nediabetici15 ani scurtarea sperantei de viata fata de nediabeticiA 6-a cauza de deces dintre toate bolile2007 diabetul zaharatThe Centers for Disease Control and Prevention, USA

Proiectii globale ale epidemiei de diabet:2007-2030 (milioane)Source: Diabetes Atlas 3rd Edition. www.eatlas.idf.org. Last accessed 25 January 2007

~90% dintre persoanele cu diabet zaharat de tip 2 sunt supraponderale sau obeze

World Health Organization, 2005. http://www.who.int/dietphysicalactivity/publications/facts/obesity

Mortalitatea diabeticilor este dubla fata de nediabeticiBalkau. Lancet 1997; 350: 1680.

Diabetul zaharat de tip 2 cauza majora de mortalitate3.45.46.66.16.02.24.86.95.18.88.62.5012345678910Excess mortality attributable to diabetes (%)AfricaAmericasEasternMediterraneanEuropeSoutheastAsiaWesternPacificMen WomenRoglic G, et al. Diabetes Care 2005;28:21305Fifth leading cause of death after infections, CVD, cancer, and accidents

Supravieuirea post-IM la femeile i brbaii diabetici este mult mai mic dect la non - diabeticiSprafka et al. Diabetes Care. 1991; 14: 537-543.

Riscul coronarian este echivalent pentru diabetici i pentru nediabeticii cu un IM in antecedenteHaffner SM et al, N Engl J Med 1998;339:229-234Cu DiabetFr Diabet

Creterea numrului de decese datorit DiabetuluiMcKinlay J et al. Lancet. 2000;356:757,761.Rata relativa a mortalitatii functie de varstaAnul140 1980

Accident vascular cerebralBoal CardiovascularCancerDiabet13012011010090807060 1982 1984 1986 1988 1990 1992 1994 1996

Design-ul cursuluiBackground fiziopatologicDefinitia diabetului zaharat si a altor categorii de intoleranta la glucozaDiagnosticul diabetuluiTipurile de diabet zaharat: definitie, etiopatogeneza, istorie naturalaTratamentul diabetului zaharatComplicatiile acute specifice ale DZComplicatiile cronice ObezitateaDislipidemiileHiperuricemiileSd. metabolic

Pancreasul endocrin - noiuni de anatomie i fiziologieInsulele Langerhans

800.000 1.500.0001 2 % din masa pancreatic totalCelule: A, B, C, D

Insulinosecreia normal, bifazicAdapted from Pratley RE, Weyer C. Diabetologia 2001; 44: 92945.

ROLUL CENTRAL AL CANALELOR KATP IN INSULINOSECRETIE

SEMNIFICAIA FIZIOLOGICA CELULELOR BETACelula -pancreatic funcioneaz ca un senzor energeticGlucokinazaMetabolismul glucozeiATPDeclanarea insulino-secreiei

INCHIDEREA CANALULUI KATP PRIN LEGAREA UNEI MOLECULE DE ATP LA UNUL DIN CELE 4 SITUSURI DE PE SUR1

Secreia insulinei Pulsatorie

Bifazic

Insulinosecreia fiziologic profil 24 ore

McIntyre et al 1964D GLUCOSE (mg/100ml)D INSULIN (mU/L) INSULIN SECRETION FOLLOWING INTRADUODENAL OR INTRAVENOUS GLUCOSEGut factors termed incretins

A DOUA CALE INSULINOSTIMULATORIE INDEPENDENTA DE CANALELE KATPGLP-1NExocitoza insulineiIntestinAcizi grasi cu lant lung (acid palmitic acid miristic)PKA - Proteinkinaza APKC Proteinkinaza CPKCPKAEsteri Acetil CoAcu lant lungVezicule de Ca2+Mecanism insulinosecretor de avarie

Controlul hormonal al glicemiei

Posibilele defecte cauzatoare de insulino-rezistenLa nivel de prereceptorInsulin anormalDegradarea crescut a insulineiPrezena n snge a antagonitilor hormonaliLa nivel de receptorScderea numrului de receptoriReceptori anormaliAlterarea unor funcii ale receptorului ( activitii tirozinkinazei, autofosforilarea receptorului)La nivel postreceptorAlterri ale sistemului efectorilor (transportorii de glucoz)Defecte ale enzimelor i.c. implicate n metab. intermediare

insulinaRc. Insul.IRSPi3 - KinazaMAPKNO, vasodilatatie Ef. anti ATSmigrare, prolif. cel. mus. netede sintezei matricialeEf. aterogenicscazutIn cazuri de IR sau insulino defic.crescutKing GL, 1999CI DE ACIUNE ALE INSULINEI LA NIVELUL CMN

DZ tip 2 deficitul insulinosecreiei postprandialePolonsky KS et al. N Engl J Med 1996; 334: 777-783

Diagnosticul diabetului zaharatLa bolnav simptomatic - cu simptome tipice de diabet zaharat - cu semne atipice sau a unor complicatii (acute sau cronice)La bolnav asimptomatic - intimplator - bilant al starii de sanatate - in cadrul unui screening . populational . pe grupuri de risc

Diagnosticul clinic al DZPoliuriePolidipsiePolifagieScdere ponderalAstenie

CRITERIILE PENTRU DIAGNOSTICUL DIABETULUI ZAHARAT simptome clasice de diabet + glicemie plasmatic ntmpltoare 200mg/dl (11,1 mmol/l)- simptomele clasice de diabet includ poliuria, polidipsia, polifagia i scderea inexplicabil n greutate; - glicemia ntmpltoare se refer la recoltare fr relaie cu ultimul prnz.Sau glicemie plasmatic pe nemncate 126mg/dl (7,0 mmol/l);- starea pe nemncate (fasting sau jeun) este definit la minim 8 ore de la ultima ingestie caloric.Sau glicemie plasmatic 200mg/dl (11,1 mmol/l) la 2 ore de la ingestia de glucoz n cadrul unui test de toleran la glucoz (TTGO);- testul se execut utiliznd 75g de glucoz dizolvate n 300 ml ap. n absena unei hiperglicemii cu semne acute de decompensare metabolic, diagnosticul trebuie confirmat prin repetarea glicemiei plasmatice pe nemncate ntr-o alt zi.

Criterii de interpretare a glicemiei bazale70-110 mg/dl normal

110-125 mg/dl glicemie bazal modificat

126 mg/dl diabet zaharat probabil; confirmarea se face dup a doua dozare la bolnavul asimptomatic

Criterii de interpretare a TTGO

VALORI DIAGNOSTICE PENTRU DIABET ZAHARAT I ALTE CATEGORII DE HIPERGLICEMIE

Snge integralPlasma venoasmg/dl (mmol/l)venoscapilarmg/dl (mmol/l)Diabet zaharat Pe nemncate sau La 2 ore dup glucoz 110 (6,1) 180 (10,9) 110 (6,1) 200 (11,1) 126 (7,0) 200 (11,1)Scderea toleranei la glucoz Pe nemncate i La 2 ore dup glucoz< 110 (

CLASIFICAREA DIABETULUI ZAHARATTip 1 (distrucia celulelor beta care conduce de obicei la insulinodeficiena absolut)autoimunidiopatic

Tip 2 (datorat predominant insulinorezistenei cu relativ insulinodeficien pn la defect predominant de secreie cu sau fr insulinorezisten)

Alte tipuri specificedefecte genetice ale funciei celulei betadefecte genetice ale aciunii insulineiboli ale pancreasului exocrinendocrinopatiiindus de administrarea de medicamente sau chimiceinfeciiforme rare de diabet mediat imunalte sindroame genetice care se pot asocia cu diabetul

Diabetul gestaional

Masa cel-proliferareneogenezahypertrofieatrofieapoptozaMasa cel in dinamicaAckermann AM, Gannon M. J. Molec. Endocrin. 2007;38:193-206.

Patogeneza diabetului zaharat de tip 1AutoimunitateProgresia distructiei beta celulareInsuficienta functiei beta celulareDependenta de insulina exogenaRisc de ceto acidoza

Etiopatogenia DZ 1 autoimunPredispoziie geneticFactor de mediu (viral, toxic, alimentar)Activare autoimun insulitScderea capacitii -secretoare; afectarea fazei secretorii iniiale, dar insulinemia plasmatic este normalDiabet clinic manifest; insulinemie plasmatic sczut, hiperglicemie, apar simptomeleApariia complicaiilor

Factorii de risc implicai n patologia diabetului zaharat tip 2Modified from Kahn R. Diabetes. 1994;43:1066-1084.6050403020GeneAmbient Diabetogene primare secundare Gene legate de diabetNormalDeficienta de secretiea insulineiInsulino-rezistenDiabet tip II Obezitate Diet Activitate fizicvrst (ani)

Peste 80% dintre pacientii care evolueaza spre diabet zaharat de tip 2 sunt insulino-rezistentiInsulin resistant; low insulin secretion (54%)Insulin resistant; good insulin secretion (29%)Insulin sensitive; good insulin secretion (1%)Insulin sensitive; low insulin secretion (16%)83%

Haffner SM, et al. Circulation 2000; 101:975980.

ACANTHOSIS NIGRICANS

Patofiziologia diabetului zaharat de tip 2Decreased glucose uptake Impaired insulin actionUnsuppressed glucose production Impaired insulin actionHyperglycemiaImpaired insulin secretion

Cum se combina insulino-rezistenta si disfunctia -celulara in geneza diabetului zaharat de tip 2?

Indicaiile screening-ului pentru DZ la subiecii asimptomatici cu ajutorul glicemiei bazaleToi subiecii cu vrsta 45 ani; se va repeta la intervale de 3 aniTestarea se va face la vrste sub 45 ani i se va repeta la intervale mai scurte la: - persoane cu IMC 27 kg/m2 - cei care au rude de gradul I cu DZ - grupuri etnice cu risc crescut - femeile care au nscut copii cu greutatea peste 4,5 kg - femeile care au avut diabet gestaional - hipertensivii - cei cu HDL 35 mg/dl i/sau trigliceride 250 mg/dl - cei cu GBM sau cu STG la testri anterioare

Patogeneza diabetului zaharat de tip 2Boala poligenicaHiperinsulinemiaMalnutritie fetala formarii celulelor betaCopil cu greutate mica la nasterethrifty gene7% scaderea celuilelor beta/an

Etiopatogenia DZ 2Factori genetici transmitere poligenicRezisten crescut la aciunea insulineiHiperinsulinism funcionalDeficien n secreia insulinic hiperglicemie persistentTulburri insulinosecretorii - caracterului pulsator al insulinei - dispariia fazei precoce a rspunsului insulinic - ntrzierea secreiei de insulinScderea absolut a secreiei insulinice DZ 2 insulinonecesitant

Adapted from Lebovitz. Diabetes Reviews 1999;7(3)UKPDS Group. Diabetes. 1995; 44:1249-1258.

2-2-10-6061014Funcia beta celular (%)501007525IFG/IGTAni de la diagnosticDZ tip 2DECLINUL FUNCIEI BETA-CELULARE N DIABETUL ZAHARAT TIP 2

Lebovitz H. Diabetes Rev 1999;7:139153.Holman RR. Diabetes Res Clin Pract 1998;40(suppl):S21-S25.-Cell Function

Numeroi factori contribuie la declinul progresiv al funciei celulei pancreaticeCelula Hiperglicemie(glicotoxicitatea)Insulinorezisten Lipotoxicitate(creterea AGL, Tg)Glicarea proteinelor

Pierderea masei celulare in istoria naturala a DZ2Prentki M., Nolan CJ. J.Clin. Invest. 2006; 116:1802-1812.

INSULINOREZISTENTA SI INSULINODEFICIENTA IN DZ 2DeFronzo R et al. Diabetes Care 1992;15:318-68

FIZIOPATOLOGIA DIABETULUI ZAHARAT TIP 2

Glucose (G)

Carbohydrate

Glucose

DIGESTIVE

ENZYMES

Insulin

(I)

I

I

I

I

I

I

I

I

G

G

G

G

G

G

G

G

I

G

G

G

insulinorezisten

Adipose Tissue

Liver

Pancreas

Muscle

Diabet STGLimita glicemiei normaleRisc pentru ochi, rinichi, nervi

Risc CVDisglicemia este un factor de risc progresiv pentru evenimente CVGerstein H. 2003Epidemiologia i riscul CV n diabet

Type 2 DM is the Tip of the IcebergBeck-Nielsen H, Groop LC. J Clin Invest. 1994;94:17141721.

The Metabolic Syndrome: Historical PerspectiveReaven G. Diabetes 1988;37:1565-1607.Insulin ResistanceGlucose IntoleranceHyperinsulinemia TG HDL-CHypertension1988: Syndrome XCoronary Heart Disease

The Metabolic Syndrome: Current PerspectiveAdapted from Reaven G. Drugs 1999;58(suppl):19-20 with permission from WolthersKluwer Health.Body Size BMI Central AdiposityGlucose MetabolismUric Acid MetabolismDyslipidemiaHemodynamicNovel Risk FactorsInsulin ResistanceHyperinsulinemia+ TG PP lipemia HDL-C PHLASmall, dense LDL Glucose intolerance Uric acid Urinary uric acid clearance SNS activity Na retentionHypertension CRP PAI-1 FibrinogenCoronary Heart Disease

Defining the metabolic syndromeaWorld Health Organisation; bEuropean Group for the study of Insulin resistance; cNational Cholesterol Education Program; dInternational Diabetes Federationeor diagnosis of diabetes or hypertension as applicable; fand/or treatmentEschwege E. Diabetes Metab 2003;29:6S19-27; International Diabetes Federation

Metabolic Syndrome Increases Risk for CHD and Type 2 DiabetesExpert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.Coronary Heart DiseaseType 2 DiabetesHigh LDL-CMetabolic Syndrome

OBIECTIVELE MANAGEMENTULUI DZMentinerea sau obtinerea unei stari generale bune, a unei calitati optime a vietiiDisparitia sau ameliorarea simptomelor de hiperglicemieAtingerea tintelor controlului metabolic fara riscuriRealizarea unei HbA1c

OBIECTIVE BIOMEDICALE PENTRU CONTROLUL DIABETULUI ZAHARAT

BunLa limitPrecarGlicemia (autodeterminare) pe nemncate/preprandial postprandial [mg/dl (mmol/l)]80-110 (4,4-6,1)100-145 (5,5-8,0)111-140 (6,2-7,8)146-180 (8,1-10,0)> 140 (>7,8)> 180 (>10,0)HbA1c (%)< 6,56,5-7,5> 7,5HbA1 (%)< 8,008,0-9,5> 9,5Colesterol seric total mg/dl (mmol/l)< 200 (< 5,2)200-250 (5,2-6,5)> 250 (>6,5)Trigliceride mg/dl (mmol/l)< 150 (< 1,7)150-200 (1,7-2,2)> 200 (> 2,2)Index mas corporal (kg/m2) B F< 25,4< 24,025,0-27,024,0-26,0> 27,0> 26,0

Glicozilarea neenzimatic a proteinelor Proporional cu - conc. glucozei din sg. - durata meninerii ei

Glucoz + Protein Baz Schiff Produs Amadori AGE (advanced glycation end-products) - stabili - se acumuleaz ca atare ( RD, ND, mbtrnire ) - au locusuri specifice de aciune - pot fi identificai n diferite structuri datorit fluorescenei lor caracteristice

Hemoglobina glicatEvalueaz controlul pe termen lung al diabetului (4-6 spt.)memorie diabetic de lung duratSubfraciuni: A1a, A1b, A1c Valori normale: Hb A1 = 8% HbA1c = 4-6%Determinarea Hb A1c - cromatografic - colorimetric - radioimunologic

Corelaii ntre valorile A1c i glicemieA1c (%)Media nivelelor glicemice 6135 mg/dl (7,5 mmol/l) 7 170 mg/dl (9,5 mmol/l) 8 205 mg/dl (11,5 mmol/l) 9 240 mg/dl (13,5 mmol/l) 10 275 mg/dl (15,5 mmol/l) 11 310 mg/dl (17,5 mmol/l) 12 345 mg/dl ( 19,5 mmol/l)

ADA. Tests of glycemia in diabetes. Diabetes Care 2003; 26 (Suppl 1): S106-S108.

Triada explorarii glicemicePPG Postprandial glucoseFPGFasting GlucoseHbA1cGlucose TRIADE

Componentele cresterii HbA1cB=breakfast; L=lunch; D=dinner.Adapted from Riddle MC. Diabetes Care. 1990;13:676-686.Plasma glucose (mg/dL)3002001000Time of day (h)61218246Uncontrolled Diabetes HbA1c 8% B L D

DCCT: microvascular complications stratified by HbA1cDCCT Group. Diabetes 1995;44:96883. 24201612840123456789Mean HbA1c = 11%10%9%8%7%DCCT study time (y)Progression rate per 100 patient-yearsRisk of retinopathy progression vs. mean HbA1c

DCCT: glycaemic control with conventional and intensive insulin treatment0.050.000.150.100.450.20Density estimate0.250.300.350.401011121314Glycosylated haemoglobin (%)Intensive group: Mean HbA1c 7.1% Mean blood glucose 8.6 mmol/lConventional group: Mean HbA1c 9.0% Mean blood glucose 12.8 mmol/lDCCT Group. Diabetes 1995;44:96883.

Glycaemic control throughout EDICConventional groupIntensive group121086DCCTCloseout12345678p

Sustained risk reduction from improved controlEDIC study time (y)0123456700.10.20.30.40.5Cumulative incidenceConventional groupIntensive groupDCCT/EDIC Group. JAMA 2002;287:2563.

ECHILIBRUL ENERGETICGlucideLipideProteine Metabolismul bazalEfort fizicTEF

Macronutrieni (trofine calorigene)- glucide- proteine- lipideMicronutrieni (trofine necalorigene)- vitamine - liposolubile - hidrosolubile- minerale - macroelemente - microelementeApa (hidratare) Surse de energie

Apetitul, foamea i saietatea constituie trei poli opui ai necesitii fiziologice de supravieuire.

Foamea reprezint dorina i necesitatea imperioas de a ingera alimente, n special energetice, far discriminare. Saietatea constituie senzaia de plenitudine sau de satisfacie, att fizic ct i psihic, dat de ingestia alimentelor. Apetitul este o dorin pentru un anume aliment bogat ntr-o varietate de nutrimente cum ar fi proteine, carbohidrai. Apetitul are o conotaie personal care ine de un model cultural de alimentaie

RECOMANDRI NUTRIIONALECANTITATIVE pentru populaia sntoas exist standarde, repere pentru categorii de indivizi n funcie de vrst, sex i activitate fizic.

CALITATIVE - n funcie de repartiia nutrimentelor n raia energetic- in cont de anumite caracteristici pentru fiecare categorie de nutriment energetic- proporia P animale/vegetale- proporia acizi grai saturai/mononesaturai/polinesaturai- indexul glicemic al alimentelor (puterea hiperglicemiant)

NECESARUL CALORIC I DE PRINCIPII ALIMENTARE LA DIFERITE VRSTE

VrstaGreutateNecesar caloric (kcal/zi)Necesar de proteine (%)Necesar deglucide (%)Necesar de lipide (%) 1 an7,38201 3 ani13,413001555304 6 ani20,218301454317 9 ani28,12190135532Biei 10 12 ani36,92600135532Biei 13 15 ani49,92490135832Biei 16 19 ani54,42310135830Brbai aduli (activitate medie)65,02900135830Femei adulte (activitate medie)55,02200135830Femei gravide (ultimile 5 luni)-+350155728Femei care alpteaz (primele 6 luni)+550145729

CARACTERELE MACRONUTRIENILOR

ProteineGlucideLipideSaietateSuprimarea senzaiei de foameAport energetic (kcal/g)% din aportul energetic zilnicCapacitatea de depozitareCi metabolice spre alte compartimenteAutoreglarea (capacitatea de stimulare a oxidrii n cazul aportului excesiv)++++++4++++++++++4++++++9++++++00

DENSITATE ENERGETIC - procentajul de kcal pentru 100 g de aliment- determinant esenial al saietii- este invers proporional cu volumul alimentelor - cu ct un aliment este mai srac n lipide densitatea sa energetic este mai mic DENSITATE NUTRIIONAL- coninutul n nutrimente nonenergetice (sau de proteine) pentru 100 kcal de aliment- pentru fiecare porie de 100 kcal este preferabil ca densitatea nutriional s fie nalt - un aliment avnd o densitate nutriional optim pentru un nutriment dat va conine o mare cantitate din acel nutriment i un slab aport de lipide. REGULI N ALCTUIREA UNEI DIETE

ALIMENTAIA SNTOAS 5 CRITERIIAdecvat alimentele consumate s aduc nutrieni eseniali, fibre i energie n cantiti suficiente pentru meninerea sntii i a greutii corpului.Echilibrat nu trebuie s prevaleze un nutriment sau aliment n defavoarea altuia (respectarea proporiilor).Controlat caloric se refer la aportul energetic care trebuie s corespund nevoilor metabolice; astfel se asigur controlul greutii corporale.Moderat atenie la posibile excese alimentare precum sarea, grsimile, zahrul sau alt component peste anumite limite. moderaie, nu abstinen! Variat evitarea consumului unui anumit aliment, chiar nalt nutritiv, zi dup zi, pentru perioade lungi de timp.

RECOMANDRI NUTRIIONALE (AHA) Pine, cereale, orez, paste finoase, mmlig, 6-11 porii/zi; aceste alimente ofer glucide complexe, fibre alimentare, riboflavin, tiamin, niacin, fier, proteine, magneziu i ali nutrieni;Legume, zarzavaturi, cartofi, 3-5 porii/zi; aceste alimente conin fibre, vitamina A, vitamina C, folai, potasiu i magneziu. Se recomand a fi folosite, de cte ori este posibil, proaspete i crude.Fructe, 2-4 porii/zi; sunt o surs bogat de fibre, vitamina A, vitamina C i potasiu. Se recomand a fi consumate, pe ct este posibil, crude i proaspete.Carne, pete, fasole boabe, ou i fructe oleaginoase, 2-3 porii/zi; aceste alimente sunt bogate n proteine, fosfor, vitamina B6, vitamina B12, zinc, magneziu, fier, niacin i tiamin. Se recomand consumul de carne de pui, curcan, carne slab de porc sau de vit i pete.Lapte, iaurt, brnz, 2-3 porii/zi; aceste produse au avantajul de a fi bogate n calciu, riboflavin, proteine, vitamina B12, iar cnd sunt fortificate i n vitamina D i A.Grsimi, uleiuri i dulciuri, moderat, zahrul i grsimea sunt bogate caloric dar, n acelai timp, sunt srace n nutrimente, ceea ce justific limitarea consumului lor.

RECOMANDRI NUTRIIONALE (OMS)Lipide 30% - lipide saturate7-10%- lipide mononesaturate10-15%- lipide polinesaturate 10%- colesterol 300 mg/ziGlucide50-55%Proteine15-20%NaCl 5 g/zi

ECHIVALENE ALIMENTARE CANTITATIVE PENTRU O PORIE

Cte porii din fiecare etaj al piramidei ar trebui s consumai zilnic?1 porie1 unciePentru 1.600 kcal.Pentru 2.200 kcal.Pentru 2.800 kcal.

CONINUTUL PROTEIC AL DIVERSELOR GRUPE DE ALIMENTE

AlimentulProteine (g/100g aliment consumabil)1. Carne ( vit, porc, pasre, pete)15-222. Mezeluri ( salam, crnai, unc)10-203. Brnzeturi15-304. Lapte de vac3,55. Ou146. Pine7-87. Paste finoase, gris, orez, fin de gru9-128. Fasole, linte, mazre, soia (boabe uscate)20-349. Nuci17

CONINUTUL DE AMINOACIZI ESENIALI

Aminoacidg/100 gnecesarmg/kg/zigruSoiaCartofOrezFasoleCombinaiecereale + leguminoaseFenilalanin144,94,94,05,35,25,25Izoleucin10,53,64,53,84,64,24,4Leucin147,37,36,09,07,68,4Lizin123,16,44,83,97,25,55Metionin + cistin131,61,31,32,31,01,65Triptofan3,51,21,33,81,51,01,25Valin104,84,81,66,34,65,45

CONINUTUL LIPIDIC AL DIVERSELOR GRUPE DE ALIMENTE

Tipuri de acizi graiCarneUleiuri i alte grsimiLapte i produse lactateLeguminoase uscate i fructe oleaginoaseOuAlte alimenteAcizi grai saturai393420223Acizi grai mononesaturai35488423Acizi grai polinesaturai18682626

Acizi graiNatura grsimiiPorcVitPasreUntOuPorumbSoiaMsline1. Acizi grai saturai butiric5,5 capric3 lauric23,5 miristic1,53712 palmitic272925282512,511,513 stearic13,521613102,542,5 arahic0,50,52. Acizi grai mononesaturai- palmit oleic33831 oleic43,5413628,5502924,5743. Acizi grai polinesaturai- linoleic10,521411055539- linolenic0,50,520,570,5- arahidonic0,53

Exemple de index glicemic

REPARTIIA NUTRIMENTELOR PE MESEChevallier L, 2003

Glucide cu index glicemic micGlucide cu index glicemic mareLipide Proteine Mic dejun

Prnz

CinaDa

Da

ModeratModerat

Moderat(dup o mas bogat n fibre)

Nu Moderat(colesterol alimentar)

Cantitate redus

Da(acizi grai polinesaturai)Da

Da

Da

REGULI N ALCTUIREA UNEI DIETEDieta prescris nu trebuie s fie nociv:- s aduc nutrimentele plastice i energetice n cantiti adecvate;- valoare nutriional bun.

Modificri prudente ale obiceiurilor alimentare:- obiceiuri determinate prin interogatoriul alimentar;- evitarea producerii frustraiilor inutile.

Rezultate controlate periodic.

PRESCRIPII DIETETICE POSIBILEPrescripia pozitiv a tuturor alimentelor indispensabile i echivalenele lor- las subiectului posibilitatea de a le adapta la gusturile i obiceiurile sale

Prescrierea n ntregime a unui regim personalizat- pornete de la prescripiile medicale- ine cont de datele i preferinele pacientului- necesit o perioad lung de timp i programe computerizate

TRATAMENTUL DIETETIC N DIABETUL ZAHARATRespectarea etapelor alctuirii unei dieteAtenie distribuirea caloriilor pe cele 3 principii energetice i pe meseSuplimentarea cu vitamine i minerale este necesar doar la - pacienii ce urmeaz un regim hipocaloric perioade lungi de timp- n condiiile creterii necesarului energetic (sarcin, lactaie, afeciuni intercurente)

Cntarul instrument indispensabil persoanei cu DZ!

ETAPELE ALCTUIRII UNEI DIETEPrecizarea caracteristicilor generale ale dieteiCalculul aportului caloricDistribuia caloriilor pe cele trei principii energetice i a macronutrienilor n grame.Alegerea alimentelorDistribuia principiilor energetice pe numrul de mesePregtirea corect a alimentelor (reguli de gastrotehnie)

INDIVIDUALIZAREA DIETEI!

TRATAMENTUL DIETETIC N DIABETUL ZAHARAT TIP 2Monitorizeaz glicemia i medicaieCrete activitatea fizicControlul glicemicModific cant.de grsimiingeratRespect orarulmeselorCrete preocupareade selecie aalimentelorRestrnge caloriile pentru normalizareagreutii Schimb stilul de via

Valori int DZ tip 2 (IDF)IDF Guidelines. Diabet Med 1999;16:716-30

TRATAMENTUL DIABETULUI ZAHARAT TIP 2Dup DeFronzo RA. Br J Diabetes Vasc Dis. 2003;3(suppl 1):S24S40Hiperglicemie progresia bolii

New Drug Targets for Type 2 DiabetesNature 414, 821 - 827 (2001)

DIABETUL ZAHARAT TIP 2 OPIUNI TERAPEUTICEinsulinorezistena disfuncie -celular

Metformin Sulfoniluree TZDs Meglitinide Hiperglicemie inhibitori de insulinoterapie glucozidaz TZD?

Digestia i absorbia HC reducerea masei -celulare

tratamentul obezitii i al dislipidemiei

CARACTERISTICI DEZIRABILE ALE MEDICAIEI ANTIHIPERGLICEMICE ORALE

Control glicemic durabil Fr risc de hipoglicemie Aciuni benefice asupra metabolismului lipidic Tolerabilitate bun i profil de siguran Regim simplu de dozare Util la un numr mare de pacieni cu DZ 2 Reducerea morbiditii/mortalitii cardiovasculare i microvasculare

Terapia n DZ tip 2Tratament nefarmacologicADOmonoterapieADOcombinaiiInsulin la culcare+/- ADOInsulinoterapie Decompensare metabolic acut

INSULINOREZISTENTA SI INSULINODEFICIENTA IN DZ 2DeFronzo R et al. Diabetes Care 1992;15:318-68

Chris Rhodes Ph.D.PNRI, Seattle, WA.Type-2 Diabetes - A Question of Balance -

Ce este exact ?disfunctia -celularaReducerea masei celulareDisfunctia progresiva a celulei ambelesausau

DZ TIP 2 AFECIUNE PROGRESIVn evoluie, majoritatea persoanelor cu diabet vor necesita insulin pentru obinerea controlului glicemic optim!

Secreie de insulinDepolarizareCanale KATP nchiseAshcroft, Gribble, Diabetologia (1999) 42: 903-919SulfonilureeInflux de Ca2+ Ca2+glucozSuIfonilureele mod de aciune pancreatic

Caracteristicile principalelor SU utilizate n diabetul zaharat de tip 2

Sulfamida hipoglicemiant

Alte denumiri comerciale

T 1/2 (ore)

Durata de aciune

Doza zilnic (mg)

Eliminare urinar (%)

Risc hipo

Sulfonilureice din generaia I

Tolbutamid

Orinaze

7

6-10

500-3000

100

+++

Clorpropamid

Diabinese

35

24-72

100-500

90-95

++++

Sulfonilureice din generaia II

Glibenclamid

Glibenclamid micronizat

Maninil, Daonil Euglucon

Maninil 1,75; 3,5

5

12-16

2,5-15

1,75 10,5

50

++++

Glipizid

Glipizid GITS

Minidiab Glucotrol

Glucotrol XL

6

12-14

5-40

2,5 - 20

70

+

Gliclazida

Gliclazid MR

Diamicron Diaprel, Predian

Diaprel MR 30

10

6-12

40-320

30 - 120

60-70

+

Gliquidona

Glurenorm

2

5-7

15-90

5

+

Glimepirida*

Amaryl

7

10-12

3-6

80

+

* Considerat de unii autori prima sulfamid hipoglicemiant de generaia a treia dat fiind existena unor efecte periferice (scdere glicemic cu minim cretere a insulinemiei).

MECANISMELE ACIUNII ANTIHIPERGLICEMICE A METFORMINULUIScderea produciei hepatice de glucoz prin diminuarea glicogenolizei i a gluconeogenezeiStimularea captrii musculare a glucozei mediat de insulinCreterea utilizrii splanhnice a glucozeiScderea absorbiei intestinale a glucozei Inhibiia lipolizei i scderea nivelelor de acizi grai liberi, urmat de ameliorarea ciclului RandleMecanismele celulare ar fi :Creterea legrii insulinei de receptoriStimularea activitii tirozin-kinazei a receptorilor insuliniciAmplificarea transportului celular al glucozei prin activarea transportului GLUT-4Creterea activitii glicogen sintetazei

CONTRAINDICAIILE METFORMINULUI N TERAPIA PERSOANELOR CU DIABET ZAHARAT TIP 2Insuficien renal: creatinina seric 1.4 mg/dl la femei sau 1.5 mg/dl la brbaiInsuficien cardiac congestiv care necesit farmacoterapieHepatopatii cronice cu transaminaze ce depesc de 3 ori valoarea superioar a normaluluiBolnavii peste 80 ani dac clearance-ul scade sub 70 ml/minSarcina i lactaiaDiabetul zaharat tip 1Persoanele dependente de alcool sau cu consum excesiv de alcoolTraumatisme severe, infecii sistemice, ocDeficit de vitamina B12

TIAZOLIDINDIONELE Activatori ai PPARCresc insulinosensibilitatea la nivel adipocitar i hepaticEfecte pe metabolismul glucidic i lipidicEfecte asupra adipogenezei i homeostaziei energeticeImplicare n inflamaie i aterotromboz

TZD + PPARin celula adipoasaStocaj mai eficient a AGL in adipocite nivelul circulator al AGL imbunatatesc metabolismul glucidic in ficat si muschi protectie -celulara de efectele toxice ale AGL reduce suprasarcinape pancreas

Success of controlling type 2 diabetesReduction in insulin resistanceImprovement in -cell function(delay disease progression)

Beneficiile fiziologice ale agonistilor PPARPPAR agonist stocare mai eficienta a AGLMai putini AGL in Pancreasimbunatateste functia -celMuschi imbunatateste actiunea insulinei creste captarea glucozeiFicatdescreste productia de glucoza

DEFINITION OF INCRETINSGut-derived factors that increase glucose-stimulated insulin secretion

In cret in Intestine Secretion Insulin

Creutzfeldt. Diabetologia. 1985;28:565.

Actions of GLP-1Pancreas: Insulin GlucagonStomach: MotilityHypothalamus: Appetite

Inhibitorii DPP-4Aport alimentarEliberare de GLP-1GLP-1 biologic activInhibitor DPP-4GLP-1 inactivDPP-4Rothenberg P et al. Diabetes 2000;49(suppl 1):A39.

GLP-1 therapy:Mimicking physiologySource: Kieffer & Habener (1999): Endocrine Reviews 20: 876-913

PHARMACOLOGIC AGENTS

Endodermal precursorPancreatic precursorEndocrine precursorsExocrine precursorInsulinGlucagonExocrineDuctalTime?Lineage relationships during pancreatic developmentLiverDuodenumJensen and Jensen, 2002.

SOURCES OF -CELLS FOR TRANSPLANTATIONAckermann AM, Gannon M. J. Molec. Endocrin. 2007;38:193-206.

AVANTAJELE SI DEZAVANTAJELE ADO

Clasa

Avantaje

Dezavantaje

Sulfonilureice

Cresc secretia de insulina (diabetic normo sau subponderal)

Pret scazut

Hipoglicemie

Crestere in greutate

Meglitinide

Cresc secretia de insulina (diabetic normo sau subponderal)

Scad glicemia postprandiala

Mai putine hipoglicemii decit sulfonilureicele

Necesita doze zilnice multiple

Scumpe

Biguanide

Nu determina hipoglicemie in monoterapie

Nu determina crestere in greutate

Efect potential benefic asupra profilului lipidic

Amelioreaza utilizarea insulinei (la obezi)

Efecte secundare gastro-intestinale

Contraindicate in afectiuni frecvente la virstnici: insuficienta renala, insuficienta cardiaca

AVANTAJELE SI DEZAVANTAJELE ADO (continuare)

Clasa

Avantaje

Dezavantaje

Inhibitori de alfa-glucozidaza

Nu determina hipoglicemie in monoterapie

Nu determina crestere in greutate

Absorbtie sistemica redusa

Scad glicemia postprandiala

Efecte secundare gastrointestinale

Necesita multiple doze zilnice

Determina o scadere mai mica a HbA1c decit alte clase de medicamente

Tiazolidindione

Amelioreaza utilizarea insulinei (la obezi)

Efect pozitiv asupra trigliceridelor si HDL

u determina hipoglicemie in monoterapie

Crestere in greutate

Crestere a LDL

Necesita o monitorizare frecventa a functiei hepatice

Scumpe

INDICATIILE INSULINOTERAPIEI in DZ2Insulinoterapie definitivaDZ tip 1(LADA)DZ tip 2 la care medicatia orala in asociere si la doze suficiente nu induce controlul glicemic propus Complicatii cronice evolutiveInsuficienta hepaticaInsuficienta renalaInsulinoterapie temporaraAfectiuni acute: IMA, infectii cu diferite localizariInterventii chirurgicale (pre-, intra- si postoperator)SarcinaComa hiperglicemica hiperosmolara

Lebovitz HE, Therapy for Diabetes Mellitus and Related Disorders, 2004

Idealized insulin effect provided by flexible multiple-dose regimensLebovitz HE, Therapy for Diabetes Mellitus and Related Disorders, 2004

Lebovitz HE, Therapy for Diabetes Mellitus and Related Disorders, 2004Idealized insulin effect provided by flexible multiple-dose regimens

Idealized insulin effect provided by split-mixed insulin regimensLebovitz HE, Therapy for Diabetes Mellitus and Related Disorders, 2004

Idealized basal insulin effect provided by a bedtime injectionLebovitz HE, Therapy for Diabetes Mellitus and Related Disorders, 2004

n 2006, ADA i EASD au elaborat primul Consens Internaional privind managementul hiperglicemiei.

INTELE HBA1C PENTRU CONTROLUL GLICEMICNivelele HbA1c ar trebui s fie ct mai aproape posibil de cele normaleNivelul int minimal: < 7%

Nivelele-int ale HbA1c sunt 6.5% USA > 7%

NIVELELE HBA1c LA CARE SE INIIAZ ORI SE MODIFIC TRATAMENTULNathan DM, et al. Diabetologia 2006;49:171121NormalControlat Necontrolat < 6%

ALEGEREA AGENTULUI TERAPEUTICNormalDiabet necontrolatHbA1c < 6%< 7.5%> 8.5%SE ADAUG UN AGENTcu potenial mai redus descdere a glicemiei ori cu debut mai lent al aciuniiSE ADAUG UN AGENT cu efect mai puternic de scdere a glicemiei sau se iniiaz terapia combinatNathan DM, et al. Diabetologia 2006;49:171121

2006: MANAGEMENT ACTIV I INTRODUCEREA PRECOCE A INSULINEI BAZALEModificat dupa Nathan DM, et al. Diabetologia 2006;49:171121HbA1c 7%HbA1c 7%HbA1c 7%OSV+METMET+ Insulina BazalaMET + SUMET + TZDMET + InsulinaIntensificatMET + SU +Insulina BazalaMET + SU+ TZDMET + TZD +Insulina BazalaInsulina Intensificat +MET + TZD

3 TREPTE PENTRU MENINEREA CONTROLULUIAdaptat dupa Nathan DM, et al. Diabetologia 2006;49:171121Percepia urgenei de a trata mai eficient i mai repede Optimizare stil viata (HbA1c 12%) Metformin (HbA1c 1.5%) TREAPTA 1 terapia iniialTREAPTA 2 dup 23 luni se adaug al doilea agentTREAPTA 3 dup 23 luni se ajusteaz tratam. Insulina bazala (HbA1c 1.52.5%) Sulfonilureice (HbA1c 1.5%) Tiazolidindione (HbA1c 0.51.4%) Se incepe ( intensifica) insulino terapia Se adauga al treilea agent oral daca este cost-eficient DZ tip 2 este o boal progresiv Adugarea medicaiei este regula pentru a menine intele terapeuticeInsulina este cea mai eficace

ABCs of coronary preventionAdapted from Cohen JD. Lancet. 2001;357:972-3.

BBeta-blockade Blood pressure control

AAspirin ACE inhibition A1C control

CCholesterol management

DDietDont smoke

EExercise

URGENELE HIPERGLICEMICE N DIABETUL ZAHARATCETOACIDOZA DIABETICSTAREA HIPERGLICEMIC HIPEROSMOLAR

elemente comune: - insulinodeficiena - hiperglicemia deshidratarecetoacidoza diabetic - insulinodeficien absolut + hormonilor de stres - cetoz, acidozstarea hiperglicemic hiperosmolar - insulinodeficien relativ - hiperosmolaritate- fr cetoz, fr acidoz

FORMULE NECESAREOsmolaritatea plasmatic:2[Na+ (mEq/l) + K+ (mEq/l)] + glicemia (mmol/l) + ureea (mmol/l)Gaura anionic:(Na+ + K+) (Cl- + HCO3- ) = 16

Cauze:Insulinodeficiena absolut ntreruperea insulinoterapiei cetoacidoz inaugural (20%) Insulinodeficiena relativ afeciuni intercurente/coexistente: infecioase (pneumonii, infecii urinare, sepsis) accidente vasculare cerebral infarctul miocardic acut pancreatita acut embolia pulmonar ocluzia intestinal, tromboza a. mezenterice gangrena diabetic endocrinopatii: tireotoxicoza, sindromul Cushing, acromegalia iatrogen (corticoizi, simpatomimetice) sarcin, stresCETOACIDOZA DIABETIC

Cetoacidoza diabeticHiperglicemie Acidoz metabolicCetoz diabet zaharat HHS STG hiperglicemia de stres acidoza lactic acidoza uremic acidoza hipercloremic acidoza drog-indus cetoza alcoolic cetoza de foameTRIADA CETOACIDOZEI DIABETICEKitabchi AE i colab, 2001

CETOACIDOZA DIABETICMecanisme implicate n geneza comei ceto-acidozice

CETOACIDOZA DIABETIC -

CETOACIDOZA DIABETIC ESTE O URGEN MAJOR!

Cetoacidoza diabetic poate ucide dar moartea poate fi prevenit prin:Diagnostic precoceMonitorizareAplicarea ghidurilor terapeutice

TRATAMENTUL URGENELOR HIPERGLICEMICEHIDRATAREINSULINGLUCOZ (GIK)POTASIUTerapie adiional (antibioterapie, O2, etc)BicarbonatFosfatKahn CR, 2000

TERAPIA DE REHIDRATARE LA PACIENII CU CETOACIDOZ DIABETICSF n primele 4 oreSG la glicemie 250 mg/dl

Joslins Diabetes Mellitus, 2005

Ora Volum Prima h 1hA 2-a orA 3-a orA 4-a orA 5-a orTotal primele 5 oreOrele 6-121litru1l500 ml - 1l500 ml 1l500 ml 1l3,5 5l250 500 ml/h

TERAPIA CU INSULINIniial 6-10 U insulin rapid iv (sau 0,1 U/kg)Se evalueaz glicemia la fiecare orScderea glicemiei cu 10% din valoarea iniial (70 mg/or)Lips de rspuns mrire doza de insulinScdere prea brusc 0,05U/kg/or

TERAPIA CU POTASIUSe monitorizeaz la 1-2 oreK+ 3,5 mmol/l se administreaz 40mmol/h (diureza prezent)K+ = 3,5-4,5 mmol/l se administreaz 20 mmol/hK+ = 4,5-5,5 mmol/l se administreaz 10 mmol/hK+ 5,5 mmol/l se ntrerupe administrarea K+

ALTE TERAPIIbicarbonatul - cu pruden - la pH 6,9 7Glicemia 250 mg/dl soluie GIKla pacienii cu hiperosmolaritate: soluii hipoosmolare, heparin TA 100 mmHg dup 2 ore de perfuzie soluii coloidale Sonda gastric, sond urinar

TRATAMENTUL CETOACIDOZEI - complicaii i efecte adverse - Hipoglicemia (glicemie 50 mg/dl) monitorizare glicemie, doze mici de insulin, soluii GIK;Hipokalemia (K+ 3 mEq/l) monitorizare ecg, laborator din or n or;Alcaloza metabolic ;acidoza paradoxala a lcr utilizare prudent a bicarbonatului;Insuficiena cardiac congestiv monitorizare fluide, diurez, dispnee, raluri pulmonare, msurare PVC;Recurene de cetoacidoz insuficiena tratamentului insulinic; Edem cerebral evitat prin insulinoterapie n doze mici, pruden n adm. bicarbonatului i a sol. hipotone;Alte complicaii AVC, IMA, nefropatie acut tubulointerstiial, colaps, tromboembolii, aspiraia de coninut digestiv, sindrom de detres respir., infecii.

A review of the epidemiology of diabetes carried out by Zimmet et al. found that, as a global phenomenon, the prevalence of diabetes is predicted to increase from 189 million in 2003 to 324 million by 2025, an increase of 72%.1 Type 2 diabetes alone has reached epidemic proportions and affects approximately 4.0% of adults worldwide. The prevalence is increasing steadily and is expected to affect 5.4% of adults by the year 2025.2 In particular, the increase in type 2 diabetes is seen among younger people and in developing countries. Indeed, a disproportionate number of diabetic patients live in the Asia-Pacific region; approximately 50 million people with diabetes live in India and China compared with 18 million in the USA.3 Wild et al. reviewed the number of individuals with diabetes globally in 2000 and found that approximately 171 million people had the disease. Extrapolation of these data, taking into consideration population growth, the increasing age of the population and changing demographics of people developing diabetes (lifestyle, diet), led to estimates that by 2030 the number of people with diabetes globally will exceed 366 million, an increase of 114% since 2000.3In summary, these data provide an updated quantification of the current and growing public health burden of diabetes across the world. The human and economic costs of this epidemic have severe implications for healthcare resource use.

1. Zimmet P, et al. Preventing Type 2 diabetes and the dysmetabolic syndrome in the real world: a realistic view. Diabet Med 2003;20:693702.2. King H, et al. Global burden of diabetes, 19952025: prevalence, numerical estimates, and projections. Diabetes Care 1998;21:141431.3. Wild S, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27:104753.The World Health Organization reports that around 90% of individuals with type 2 diabetes are overweight or obese.1Fat distribution in the body may be either abdominal (android or central obesity often referred to as apple-shaped) or affect the lower body (mainly thighs and buttocks; gynoid obesity often referred to as pear-shaped).2Central obesity (indicated by, for example, high waist:hip ratio; that is waist:hip ratio > 0.90 for men, > 0.85 for women) is a strong risk factor for insulin resistance.31 World Health Organization, 2005. http://www.who.int/dietphysicalactivity/publications/facts/obesity2Basdevant A, et al. Presse Med 1987; 16:167170.3Ascaso JF, et al. Eur J Intern Med 2003; 14:101106.This study, conducted by Roglic and co-workers, used a computerized generic formal disease model called DisMod II to estimate excess global mortality attributable to diabetes. The results showed that diabetes-related deaths were 3 times more frequent than international estimates produced using death certificates. Differences in mortality rates between sexes were also highlighted. A greater proportion of excess deaths in women was observed, attributable to their lower background mortality rates. Overall, women with diabetes had a greater increase in the absolute risks of dying than men with diabetes.Diabetes is often associated with excess and linked to affluent countries. However, the results of this study suggest that approximately 1 in 10 deaths in economically productive individuals aged 3564 years in most developing countries can be attributed to diabetes. Before these data were available, diabetes was the eighth cause of death; subsequently, diabetes can be considered the fifth in the list of deaths by disease after cardiovascular disease, cancer, and injuries. Furthermore, the authors predict that deaths related to hyperglycemia would have been more frequent had impaired glucose tolerance been taken into account.

Roglic G, et al. The burden of mortality attributable to diabetes: realistic estimates for the year 2000. Diabetes Care 2005;28:21305.

This publication from a Finnish population-based study are the basis for the classification of diabetes as a CHD equivalent in ATP III, as this study demonstrated that the CHD risk of patients without diabetes that already have suffered from myocardial infarction is comparable to the risk of patients with diabetes that had been free of CHD at baseline. However, as these data come from the 1980s, they may not reflect any more the current therapeutic situation, as have suggested some data from the Heart Protection Study.Diabetul de tip 2 este acum considerat a fi o epidemie rspndit n toat lumea cu o prevalen mai mare de 135 milioane de pacieni n anul 2000; diabetul de tip 2 este de asemenea strns corelat cu morbiditatea i mortalitatea CV crescut:Acestea sunt datele din America de Nord publicate n The Lancet care arat rata mortalitii n funcie de vrst pentru majoritatea bolilor importante n ultimii 20 de ani comparativ cu 1980. Putei vedea datele ncurajatoare n ce privete rata mortalitii n funcie de vrst pentru accidentul vascular cerebral i bolile cardiovasculare a sczut semnificativ n ultimii 20 de ani, reflectnd utilizarea agenilor antihipertensivi pe scar larg, aspirina i terapia cu statine. Putei observa c rata mortalitatii datorate cancerului a rmas exact aceeai n ultimii 20 de ani. n ce privete diabetul, rata mortalitii n funcie de vrst crete n ritm alarmant n ciuda informaiilor deinute despre beneficiile terapiei interventionale.

In the normal individual, the typical meal-related insulin response to glucose is characterised by a short and sharp rise, which then rapidly returns to basal levels. We have seen before that in type 2 diabetes, beta-cell function declines progressively, affecting first-phase insulin response at an early stage, and thus disrupting the biphasic insulin profile.

1.Pratley RE, Weyer C. Diabetologia 2001; 44: 92945.

The incretin effect describes the enhanced secretion of insulin observed following energy (usually glucose) ingestion via the enteral vs. parenteral routes. The incretin effect is diminished in human subjects with type 2 diabetes.

The underlying abnormality in type 2 diabetes is the failure of insulin secretion in response to meals - lower peak and delayed secretion. Prandial Glucose Regulation is the most physiologic way to compensate for this abnormality: it is to provide insulin when, and only when, its needed - i.e. at mealtime. There is no defect in basal insulin secretion in type 2 diabetes - excluding end-stage diabetes.The 7-year follow-up of the San Antonio Heart Study revealed that 195 of 1,734 subjects (11%) progressed to type 2 diabetes.These 195 converters could be characterized into four groups:insulin resistant; low insulin secretion (54%)insulin resistant; good insulin secretion (29%)insulin sensitive; low insulin secretion (16%)insulin sensitive; good insulin secretion (1%).In the study, insulin resistance was most strongly associated with progression to type 2 diabetes, with 83% of converters being insulin resistant.The lowest risk of developing type 2 diabetes was in subjects who were insulin sensitive combined with good insulin secretory capacity (1%).Haffner SM, et al. Circulation 2000; 101:975980.Over time, changes in insulin resistance and secretion lead to the onset of type 2 diabetes.In the early stages, as insulin resistance rises, there is a compensatory increase in insulin secretion and glucose levels remain normal (normoglycemia).In the long term, however, as the b-cells begin to fail, insulin secretion falls, IGT and hyperglycemia become apparent and frank type 2 diabetes develops.IGT may be defined as higher than normal blood glucose levels, but not high enough to be called diabetes. People with IGT may or may not go on to develop diabetes. Glucose levels both before (fasting) and after (post-prandial) meals increase steadily as the individual progresses from normoglycemia to IGT and, finally, type 2 diabetes.International Diabetes Center (IDC), Minneapolis, 2000. Key Point: - Based on an extrapolation of data from the UKPDS, at the time of diagnosis of type 2 diabetes, -cell function is likely already markedly decreased and continues to decline despite treatment. This suggests that the process of -cell dysfunction as a result of insulin resistance is occurring years before the clinical diagnosis of diabetes is made.

Citation:Holman RR. Assessing the potential for alpha-glucosidase inhibitors in prediabetic states. Diabetes Res Clin Pract 1998;40 (suppl):S21-5.Lebovitz H. Diabetes Rev 1999;7:139153.

Dual defect of type 2 diabetes: treating a moving targetThe complex pathophysiology of type 2 diabetes underlies the loss of glycaemic control in type 2 diabetic patients receiving oral antidiabetic monotherapy. A remorseless progression of the dual endocrine defects of insulin resistance and b-cell dysfunction begins years before the diagnosis of type 2 diabetes and occurs throughout the evolution of dysglycaemia. Initially, insulin resistance causes the glucose-lowering actions of insulin to be blunted, so that the pancreas secretes more insulin to overcome the deficit. At this stage the subject may develop impaired glucose tolerance, but is not yet diabetic. As insulin resistance progresses, the pancreas is no longer able to secrete enough insulin to control glycaemia, and increased hepatic glucose output and reduced glucose disposal by muscle and fat contribute to the chronic fasting and postprandial hyperglycaemia characteristic of type 2 diabetes. Adapted from DeFronzo RA, Bonadonna RC, Ferrannini E. Diabetes Care 1992;15:318-68The metabolic syndrome: historical perspectiveThe clustering of cardiovascular risk factors including obesity, hypertension, and dyslipidemia has been noted since 1970. However, Professor Reaven at Stanford, in his Banting lecture in 1988, made the important observation that this cluster of risk factors may be linked to insulin resistance. Professor Reaven called this entity "Syndrome X," but it is more commonly called the metabolic syndrome, or the insulin resistance syndrome. Note that Professor Reaven listed glucose intolerance rather than diabetes, since subjects who developed type 2 diabetes need a second deficit, which is impaired insulin secretion. As a result, many or most individuals with insulin resistance will not actually have type 2 diabetes. In his 1988 Banting lecture, Professor Reaven attempted to show that people can have the insulin resistance syndrome even without obesity. However, other investigators such as Desprs have noted that insulin resistance occurs most often in combination with increases in visceral fat. Not all of the components described in the 1988 Banting lecture are equally strongly related to insulin resistance. A number of techniques including factor analysis have been used to suggest that hypertension has no or only a very weak relationship to insulin resistance.

References:Reaven GM. Banting lecture 1988: role of insulin resistance in human disease. Diabetes 1988;37:1595-1607. Pouliot MC, Desprs JP, Lemieux S, Moorjani S, Bouchard C, Tremblay A, Nadeau A, Lupien PJ. Waist circumference and abdominal sagittal diameter: best simple anthropometric indexes of abdominal visceral adipose tissue accumulation and related cardiovascular risk in men and women. Am J Cardiol 1994;73:460-468. Hanley AJG, Festa A, DAgostino RB Jr, Wagenknecht LE, Savage PJ, Tracy RP, Saad MF, and Haffner SM. Metabolic and inflammation variable clusters and prediction of type 2 diabetes: factor analysis using directly measured insulin sensitivity. Diabetes 2004;53:1773-1781.The metabolic syndrome: current perspectiveSince the 1998 Banting lecture, a number of new candidates for the metabolic syndrome/insulin resistance syndrome/"syndrome X" have been recognized. These additional candidates have included small, dense LDL and a group of novel risk factors including elevated CRP levels, plasminogen activator inhibitor1 (PAI-1), and fibrinogen. Other investigators have noted that insulin resistance occurs in women with polycystic ovarian syndrome, and some authors are now making an association between insulin resistance and nonalcoholic fatty liver disease (NAFLD). In a more recent review, Professor Reaven acknowledges the importance of visceral adiposity. Additional abbreviations: PP lipemia = postprandial lipemia; PHLA = postheparin lipolytic activity; SNS = sympathetic nervous system.

Reference:Reaven G. Syndrome X: 10 years after. Drugs 1999;58(suppl 1):19-20. Defining the metabolic syndromeUntil April 2005, 3 available definitions of the metabolic syndrome required the presence of dysglycaemia or insulin resistance plus 2 other cardiovascular risk factors. The IDF have now proposed a unified definition, in order to facilitate comparisons between studies, and the development of treatment strategies. This requires central (abdominal) obesity to be present, in addition to two other risk factors. Cut-off values for diagnosis of the new definition of the metabolic syndrome are shown below: Waist circumference >94 cm (men) and >80cm (women)Plus 2 or more of Triglycerides >1.7 mmol/L (150 mg/dL) HDL-C: 85 mmHg, or diagnosed or treated hypertension FPG > 5.6 mmol/L (100 mg/dL), or diagnosed type 2 diabetes

Values for Europid subjects: specific values are provided for subjects of other ethnic backgrounds: South Asian: >90 cm (men), >80 cm (women) Chinese: >90 cm (men), >80 cm (women) Japanese: >85 cm (men), >90 cm (women)

Or specific treatment for this condition.Eschwege E. Diabetes Metab 2003;29:6S19-27. International Diabetes Federation. http://www.idf.org.

Metabolic syndrome increases risk for CHD and type 2 diabetesThe NCEP has traditionally focused on high low-density lipoprotein cholesterol (LDL-C) as a risk factor for coronary heart disease (CHD). In the NCEP Adult Treatment Panel III (ATP III) recommendations published in JAMA in 2001, the NCEP suggested that the metabolic syndrome might independently predict the development of both type 2 diabetes and CHD.

Reference:Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497.In diabetes care, it is now time for all components of the glucose triad to have their place in management fasting glucose, HbA1c and postprandial glucose.[Ref, p. 677]The DCCT ended in 1993.The results demonstrated the benefits of intensive treatment and good glycaemic control. Here, the risk of retinopathy at any mean HbA1c level increased with duration of follow-up during the DCCT. The same risk of retinopathy was reached within 2.5 years at 11% HbA1c level as was reached in 9 years at a 8% HbA1c level. It appears that both degree and duration of glycaemic exposure are important determinants of the risk of retinopathy.In DCCT, over 1400 patients with type 1 diabetes were randomised to conventional or intensive insulin therapy, the latter aimed at achieving HbA1c < 6.05%. The randomisation produced a clear distinction at endpoint (49 years), with a median HbA1c of 9.02% in conventional group and 7.07% in the intensive group.At EDIC baseline, the HbA1c values for the previous intensively-treated and conventionally treated groups were 7.2% and 9.1%, respectively (p < 0.001). However, the HbA1c levels between the two previous treatment groups began to converge throughout the EDIC study. The mean HbA1c values throughout the EDIC study were 8.0% and 8.2% in the previously treated intensive and conventional groups, respectively (p = 0.002).

Despite the fact that the HbA1c levels in the intensive and conventional groups rapidly converged once they were released from the DCCT protocol, the difference in microvascular risk has persisted throughout the follow-up, suggesting that it is the patients total glycaemic exposure, not just their recent history of glycaemia, that affects their degree of risk. This doesnt mean that we can relax good control once weve achieved it (in EDIC the convergence of HbA1c was at a level similar to the intensive-treatment group in DCCT) but that its never too soon to get to good control.The primary metabolic defects of T2DM are pancreatic islet dysfunction (-cell and -cell dysfunction) and impaired insulin action (insulin resistance); another contributing factor is uncompensated glucose influx.Many of these specific problems are addressed by one or another existing class of oral antihyperglycemic drugs, each of which has distinctive mechanisms.1-Glucosidase inhibitors moderate glucose influx by delaying intestinal carbohydrate absorption, thereby mitigating postprandial glucose excursions.1 The utility of these agents depends in part on proper dietary compliance and is more effective in populations whose diet does not consist of highly processed foods. The widespread use of these agents in Japan and Spain is an excellent example of their utility in populations where a rice and fish diet is prevalent. Thiazolidinediones (TZDs) work primarily by enhancing both basal and insulin-mediated suppression of hepatic glucose production and to some extent by augmenting insulin-stimulated muscle glucose utilization.2Metformin (of the biguanide drug class) lowers glucose levels, chiefly by reducing heptic glucose production.1Sulfonylureas lower the glucose threshold for triggering -cell insulin release.1Glinides resemble sulfonylureas in enhancing acute -cell function. Their short metabolic half-lives enable them to produce brief, episodic stimulation of insulin secretion.1 Of the glinides, nateglinide is rapidly reversible, whereas repaglinide is not.No currently available therapy addresses -cell function (glucagon) and chronic -cell function.References1. Inzucchi SE. Oral antihyperglycemic therapy of type 2 diabetes: scientific review. JAMA. 2002;287-360372.2. DeFronzo RA. Impaired glucose tolerance: do pharmacological therapies correct the underlying metabolic disturbance? Br J Diabetes Vasc Dis. 2003;3(suppl 1):S24S40. Dual defect of type 2 diabetes: treating a moving targetThe complex pathophysiology of type 2 diabetes underlies the loss of glycaemic control in type 2 diabetic patients receiving oral antidiabetic monotherapy. A remorseless progression of the dual endocrine defects of insulin resistance and b-cell dysfunction begins years before the diagnosis of type 2 diabetes and occurs throughout the evolution of dysglycaemia. Initially, insulin resistance causes the glucose-lowering actions of insulin to be blunted, so that the pancreas secretes more insulin to overcome the deficit. At this stage the subject may develop impaired glucose tolerance, but is not yet diabetic. As insulin resistance progresses, the pancreas is no longer able to secrete enough insulin to control glycaemia, and increased hepatic glucose output and reduced glucose disposal by muscle and fat contribute to the chronic fasting and postprandial hyperglycaemia characteristic of type 2 diabetes. Adapted from DeFronzo RA, Bonadonna RC, Ferrannini E. Diabetes Care 1992;15:318-68Major discussion point:

INtestineSeCRETionINsulin

Creutzfeldt W, Ebert R. New developments in the incretin concept. Diabetologia. 1985;28:565-573.The number and type of treatment options being developed and that are becoming available for type 2 diabetes are expanding; however, this increased treatment choice can lead to confusion about the most effective ways to manage patients hyperglycemia and concomitant conditions. Treatment guidelines for diabetes are available in many countries, but there is a need for a standardized, more international approach to disease management to help physicians select the most appropriate treatment strategies for individual patients with varying stages of disease progression. The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have therefore combined forces to produce the first, truly international guidelines for the initial treatment and lifetime management of type 2 diabetes.

In order to emphasize the long-term health benefits of achieving and maintaining near-normal glycemic control, national diabetes organizations set increasingly strict targets for diabetes care. So much so, that the aim of current management strategies is to achieve HbA1c levels of 6.57.0%.1,2 However, this places more and more strain on healthcare providers because nearly two-thirds of diabetes patients are not at goal.3,4

1. International Diabetes Federation. A desktop guide to Type 2 diabetes mellitus. European Diabetes Policy Group 1999. Diabet Med 1999;16:71630.2. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2005;28(Suppl 1):S436.3. Saydah SH, et al. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA 2004;291:33542.4. Liebl A, et al. Evaluation of risk factors for development of complications in Type II diabetes in Europe. Diabetologia 2002;45:S238.

The latest guidelines for the management of type 2 diabetes, co-developed by the ADA and EASD, recommend that HbA1c levels in patients with diabetes should be maintained as close to the non-diabetic range as possible. Furthermore, the minimum standard of care should be HbA1c levels of 7%. In addition, the guidelines emphasize the importance of early diagnosis and timely intervention to maintain glycemic control and help improve the probability that patients will experience better long-term outcomes. Therefore, the consensus of the two associations is that, wherever possible, treatment should be initiated or changed if HbA1c levels are 7%.

Nathan DM, et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2006;49:171121.

The progressive nature of type 2 diabetes means that even if first-line treatment achieves glycemic control, inevitably further interventions will be required to address the underlying continuous decline in beta-cell function. A major factor in determining which type of treatment is the most appropriate is ambient level of glycemia. Patients with HbA1c levels > 8.5% (high glycemia) should receive treatments with greater and more rapid glucose-lowering effects or earlier initiation of combination therapy. Conversely, in patients with better glycemic control (HbA1c levels of < 7.5%), medications with less potential to lower glycemia and a slower onset of action can be considered.


The algorithm for pharmacotherapy proposed by Nathan and colleagues can be simplified and summarized as depicted above. The initial approach should include metformin, titrated to its maximally effective dose. As soon as it is evident that metformin therapy is inadequate, a second agent should be added. This can be either basal insulin for patients with poorly controlled disease (HbA1c levels > 8.5%), or oral agents such as sulfonylurea (SU) and thiazolidinediones (TZDs; glitazones) for patients who are closer to their treatment goal. Other combinations of oral agents and insulin should be considered when HbA1c levels continue to be insufficiently controlled after 23 months. The addition and intensification of insulin therapy (both basal and prandial insulin) will ultimately be required if hyperglycemia persists.


The following three-step approach to achieving and maintaining glycemic control is recommended. This graphic shows the relative glucose-lowering potential of all commonly used antidiabetes agents. Step 1 initial therapy should be a combination of lifestyle intervention and metformin therapy. Metformin is the first-choice pharmacological intervention because of its efficacy, absence of weight gain and hypoglycemia, high level of acceptance, and low cost. Step 2 additional therapy within 23 months of the initiation therapy or whenever HbA1c goal is not achieved. Basal insulin therapy should be considered for patients with HbA1c levels > 8.5% because insulin is the most effective glucose-lowering agent and can achieve reductions of up to 2.5%. Hospitalisation is not required to initiate insulin or adjust therapy. The patient is the key player and should be trained and empowered with the guidance of healthcare professionals.Step 3 further adjustments to achieve glycemic targets. This involves initiation of basal insulin if not previously used or intensification of insulin therapy using prandial insulin to control postprandial glucose excursions. In some cases another oral agent may be added but this is often ineffective and can be relatively expensive.

Nathan DM, et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2006;49:171121. 1. Cohen JD. ABCs of secondary prevention of CHD: Easier said than done. Lancet. 2001;357:972-973.

Compelling evidence from randomized clinical trials supports the use of four classes of therapies for CV risk reduction that can be remembered by a simple mnemonic, ABC1: A: ACE inhibitors Antiplatelet agents (aspirin) B: Beta-blockers BP control C: Cholesterol managementImportant lifestyle recommendations can be incorporated into the mnemonic: D: Diet Dont smoke E: Exercise

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